DMAP Pharmaceuticals and Product Brochure...DMAP Pharmaceuticals and Agrochemicals NUTRITION...
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DMAP Pharmaceuticals and Agrochemicals
NUTRITION PERSONAL &CONSUMER CARE
Smart Chemistry. Our Specialty.
Introduction Page 1
a) Physical 2b) Toxicological 2c) Handling 3d) Shipping 3e) Specifications 3
Acylation 4a) Hydroxyl groups 4b) Amine groups 11
Alkylation 14a) Hydroxyl groups 14b) Amine groups 16c) Silylation 16d) Phosphorylation 17
Heterocyclic chemistry 22a) Cyanuric acids 22b) Penicillins 22c) Pyrrolidones 22d) Solid phase synthesis 23e) Cyanation of thiols 23f) Rearrangements 24g) Vilsmeier Amidation 24h) Bischler-Napieralski cyclization 25i) Dehydration 25j) Baylis-Hillman reaction 25
Polymer chemistry 26
TACT polymers 27
Example of Preparations 28
The protection of various functionalities with acetate and tosylates, (and similar groups such as mesylates, benzoates, tritylates, etc.) is well-known. In fact, treatment of amines and alcohols with acetic anhydride in the presence of a base, such as pyridine, has been a well-established procedure since the turn of the 20th century.
An example of this can be seen when reading the old carbohydrate literature. Often, to obtain solid, crystalline derivatives of sugars and glycosides, the product was peracetylated using this methodology. This allowed comparison to known authentic compounds that were also peracetylated. In early days these comparisons were not spectral, but were by melting point and mixed melting point.
This derivitization procedure generally works well, except on sterically hindered substrates, or where the substrate is electronically deactivated.
It was not until the late 1960s that certain dialkylaminopyridine catalysts were discovered to be useful as more difficult acylations. One of these catalysts was 4- (N,N-Dimethylamino) pyridine, DMAP (1)1.
Generally DMAP enhances the rate of acylation by a factor of approximately 10,000.
There is a good review of the literature2, covering the period prior to 1968. Since that time many industrial applications have been developed for DMAP. In fact, since the review, further work has demonstrated that DMAP has many applications outside of the acylation catalysis field.
Since the resonance interaction of the electron-donating 4- (N,N-Dimethylamino)- function on the pyridine ring greatly activates the ring nitrogen toward nucleophilic substitution, DMAP is an exceptional catalyst for a host of electrophilic substitution reactions. It is a well known acylation catalyst, but it also enhances the yield, conversion and rates of many other reactions.
DMAP can also enhance formylation, carbamoylation, benzoylation, tritylation, silylation, esterification, phosphorylation, polymerization of amides, esters, urethanes and many other reactions.
DMAP finds uses in the synthesis of many pharmaceuticals, agrochemicals and general fine chemicals as well as in the flavor and fragrance, photographic, cosmetic and polymer industries.
DMAP, cas no. [1122-58-3], is registered on the following inventories:EINECS :2143535TSCA :ListedIts molecular formula is C7H10N2, with a corresponding molecular weight of 122.17. It is a colorless, crystalline solid with a melting point of around 112oC, and a boiling point of ca 160oC at 50mmHg. The solubility in water is 7.6g/100ml, (7.6% w/v) at 25oC, and it is soluble in solvents such as alkanes, chloroalkanes, aromatics, amines, alcohols and esters some of which are often used as solvents in reactions where DMAP is employed.
Toxic by all routes. Corrosive to eyes, skin and respiratory system. May cause permanent damage.R-Phrases R 23/24/25 Toxic by inhalation, in contact with skin, and if swallowed. R 34 Causes burnsS-Phrases S 7/8 Keep container tightly closed and dry. S 9 Keep container in a well ventilated place. S 22 Do not breathe dust. S 26 In case of contact with eyes, rinse immediately with plenty of water and seek medical advice. S 36/37/39 Wear suitable protective clothing, gloves and eye/face protection. S 45 In case of accident or if you feel unwell, seek medical advice immediately (show label where possible).
Some data that are available are shown below:
Test type LD50 (mg/kg)Oral (rat) 230Oral (rat) 140Oral (rat) 95Oral (mouse) 119Dermal (rat) 500aDermal (rat) 50bDermal (rabbit) 90cDermal (rabbit) 90a: 5% w/v aqueous solutionb: 12.5% w/v aqueous emulsionc: Pure material
There is no evidence of carcinogenic properties, nor is there evidence of mutagenic effects, (Ames test negative), or teratogenic effects.
c) Handling/Spillage Wear suitable protective clothing, gloves and eye/face protection. Do not scatter spilled material with high-pressure water streams. Dyke fire control water for later disposal.
Thermal decomposition will lead to release of toxic fumes of hydrogen cyanide, as well as oxides of nitrogen and carbon. Primary extinguishing media should be water spray, fog or regular foam.
Classification Toxic Solid, Corrosive, Organic, N.O.S.Class 6.1UN Number 2928Packing Group IISecondary Hazard 8
TEST UNITS DMAP TECH DMAP FLAKE/PRILLSAppearance N/A Light to dark tan powder White to slightly off-white flakes/ prills, free from visible contamination
Identity (IR) N/A Compares to reference spectrum Compares to reference spectrum
Melt point C 111.0 113.0 111.1 113.0
Water content % w/w Maximum 0.5 Maximum 0.10
Assay % w/w 99.0 101.0 99.0 101.0
Solvent % w/w Maximum 0.5 Maximum 0.10
GLC % area Minimum 99.0
Color/Clarity PT/Co Maximum 30, Clear Solution
a) Hydroxyl groups
One of the first observations that DMAP was a useful catalyst in the acetylation of sterically hindered tertiary alcohols was seen in the acetylation of 1-Methylcyclohexan-1-ol1.
Under standard acetylation conditions with acetic anhydride-pyridine at ambient temperature overnight, the acetate product (2), was only formed in 5% yield.
However, when treated with a catalytic amount of DMAP and triethylamine as base, under comparable conditions, the yield was raised to 86%. Although not optimised, using as little as 5% w/w of DMAP to substrate can often effect the transformation to a satisfactory extent. In some cases, where the acylation is somewhat trickier, heat is required to enhance reaction rates.
Another good example is seen when observing the acetylation of hydroquinone. It is known that attempted mono acetylation of hydroquinone often results in mixtures of mono- and bis-acylated products, as well as unreacted starting material. Johnston3 found that even using a protection strategy of benzylation, or benzoylation of one of the OH groups, followed by acetylation and then deprotection, only afforded the mono-acetate in 40-45% yield.
Upon the addition of 0.05% w/w of DMAP, the mono acetate was formed in 65% yield in 15-30 minutes, without the need for additional protection-deprotection steps.
It should be noted that: Generally a DMAP to substrate ratio of 1:20 is sufficient. Generally a non nucleophilic base such as pyridine or TEA should be used in stoichiometric amounts (with respect to substrate), to remove the acid produced. Generally anhydrides are superior to acid chlorides in this procedure.
Many solvents have been used, including pyridine, toluene, hexane, ethyl acetate and chlorinated solvents.
Industrial uses of DMAP in acylation are many and varied. For instance, in the synthesis of Pravastatin, a typical example of the acylation step shown below uses DMAP:
Here, pyridine is the base and the DMAP is used in approximately 6% w/w. Even after chromatography, the recovered yield was 89% of the acylated product.
Another statin or antihyperlipademic, which uses DMAP in the synthesis for the same acylation, is Simvastatin4. In the example below 2,2-Dimethylbutyryl chloride is used rather than the anhydride shown in the Pravastatin synthesis.
In fact, if the synthesis is carried out using the chiral acid chloride, then the product could actually be Lovastatin, which has the optically active ester grouping on the naphthol functionality.
Likewise, in the synthesis of Montelukast5 (3), acylation is a key step in the synthesis; in this case it is the preparation of themono-benzoylated cyclopropane derivative (4).
Note that the reduction can be done without using lithium aluminium hydride, but the more user-friendly VitrideTM (also supplied by Vertellus), as well as Pyridine (another of Vertellus products).
Even more complex molecules such as Paclitaxel, Taxotere and Docetaxel require simple acylation and/or protection. For instance in Docetaxel, DMAP is used not only in the acylation of the oxazolidinone (5), but also in the synthesis of the BOC protected amine (6).
DMAP is also used later in the synthesis when the coupling of the side chain made from (6), by reaction with 2-acetoxypropene to form the chiral oxazolidine carboxylic acid, is coupled to the macrocycle the process essentially being an esterifi